Drug-associated cues elicit craving and relapse in addicts and contribute to the progression and persistence of addiction. The objective of this research is to establish novel behavioral and pharmacological methods to effectively and persistently reduce relapse by decreasing the motivational significance of drug cues, and to elucidate the corresponding neurobiological mechanisms. We have identified drug-induced alterations in amygdala DA/cAMP-regulated signaling that promote reward-related learning and memory processes, result in stronger reward-associated memories, and that enhance behavioral control by cues acting as conditioned reinforcers. While we have focused on DA/cAMP-regulated signaling cascades, recent biochemical and pharmacological studies show that cAMP activates at least two distinct intracellular signaling targets: protein kinase A (PKA) and exchange protein activated by cAMP (Epac). Epac is highly expressed in the basolateral nucleus of the amygdala (BLA) and prefrontal cortex (PFC) but its role in brain is virtually unknown. Our new data confirm regulation of BLA- and PFC-dependent behaviors by both PKA and Epac. Here, we will test the hypothesis that both disrupted reconsolidation of cue-drug memories and enhanced consolidation of extinction can reduce cue-induced relapse. To understand the role of cAMP-regulated cellular events in these processes we will use selective activation or inhibition of PKA and Epac given after non-reinforced cue exposures to independently alter reconsolidation or extinction mechanisms. Subsequent tests will examine cue-induced reinstatement and the ability of cocaine-associated cues to act as conditioned reinforcers. Aim 1 will use amygdalar manipulations to disrupt memory reconsolidation to reduce the strength of cue-drug associations. Our data demonstrate that amygdala infusions of inhibitors of cAMP signaling after reactivation of a cocaine- paired cue can reduce both cue-induced reinstatement and responding with conditioned reinforcement, consistent with reports that cocaine-seeking behavior can be reduced by disruption of cue-drug memories. Aim 2 will use PFC manipulations (infralimbic vs. prelimbic) to enhance extinction of cocaine-associated cues. These studies will also investigate the impact and persistence of selected manipulations on newly acquired or older cue memories as well as characterize resulting alterations in cAMP/PKA/Epac activity. Aim 3 will use interventions identified in Aims 1 & 2 to discover if a combination of approaches that disrupt reconsolidation and enhance consolidation of extinction together can have more profound effects. Reductions in cue-induced reinstatement and conditioned reinforcement as well as altered context dependency of cue extinction will be examined. We will also determine if cocaine-induced alterations in cAMP/PKA/Epac activity induce persistent, maladaptive, drug-associated memories by biasing cue-drug memories to undergo reconsolidation, as opposed to extinction when reactivated. Together these studies should identify processes that underlie cue- induced craving and relapse in order to develop novel behavioral and pharmacological treatment strategies. The goal of the proposed research is to understand how cAMP-regulated signaling processes can be used to reduce the behavioral control of cue-cocaine memories through alterations in memory reconsolidation and extinction - opposing mnemonic processes that depended on subregions of the amygdala and prefrontal cortex, respectively. We will also test the hypothesis that cocaine-induced neuroadaptations in these regions may predispose cue memories to undergo reconsolidation, as opposed to extinction, and thereby contribute to the development and persistence of maladaptive drug-associated memories and their ability to precipitate cocaine-seeking and -taking behavior. Understanding these mechanisms can be used to identify novel behavioral and pharmacological treatment strategies to effectively and persistently reduce the ability of cocaine-associated cues to induce relapse in order to combat addiction.